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MCD: Cancer > Apoptosis > Flashcards

Apoptosis Flashcards

1
Q

Why is programmed cell death important?

A

Harmful cells (e.g. with viral infection, DNA damage).
Developmentally defective cells (e.g. B lymphocytes expressing antibodies against self-antigens).
Excess/unnecessary cells (embryonic development: brain to eliminate excess neurons; liver regeneration; sculpting of digits and organs).
Obsolete cells (e.g. mammary epithelium at the end of lactation).
Exploitation- chemotherapeutic killing of cells.

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2
Q

What is necrosis?

A

Unregulated cell death associated with trauma, cellular disruption and an inflammatory response.

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3
Q

What is apoptosis (programmed cell death)?

A

Regulated cell death.
Controlled disassembly of cellular contents without disruption.
No inflammatory response.

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4
Q

How does necrosis occur?

A

Plasma membrane becomes permeable.
Cell swelling and rupture of cell membranes.
Release of proteases leading to autodigestion and dissolution of the cell.
Localised inflammation.

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5
Q

What are the 2 phases of apoptosis?

A

Latent phase

Execution phase

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6
Q

What happens in the latent phase of apoptosis?

A

Death pathways are activated, but cells appear morphologically the same.

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7
Q

What happens in the execution phase of apoptosis?

A

Loss of microvilli and intercellular junctions.
Cell shrinkage.
Loss of plasma membrane asymmetry (phosphatidylserine lipid appears in outer leaflet).
Chromatin and nuclear condensation.
DNA fragmentation.
Formation of membrane blebs.
Fragmentation into membrane-enclosed apoptotic bodies.

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8
Q

What is apoptosis-like PCD?

A

Some, but not all, features of apoptosis.

Display of phagocytic recognition molecules before plasma membrane lysis.

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9
Q

What is necrosis-like PCD?

A

Variable features of apoptosis before cell lysis.

‘Aborted apoptosis’.

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10
Q

What are the 2 main types of cell death?

A

Apoptosis

Necrosis

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11
Q

What are the mechanisms of apoptotic cell death?

A 
Caspases.
Initiating the death programme:
-death receptors (extrinsic)
-mitochondria (intrinsic)
Bcl-2 family.
Stopping the death programme.
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12
Q

What are caspases?

A

Cysteine-dependent aspartate-directed proteases.
Executioners of apoptosis.
Activated by proteolysis.
Cascade of activation.

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13
Q

What are the 2 groups of caspases?

A

Initiator caspases

Effector caspases

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14
Q

What are the initiator caspases?

A

First to be triggered.
Caspase 2 and 9, motif CARD (caspase recruitment domain- localises caspase)
Caspase 10 and 8, motif DED (death effector domain- homotypic protein-protein interactions)
All contain p20 and p10 domains.

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15
Q

What are the effector caspases?

A

Caspase 3, 6 and 7.

Do not contain motifs (CARD or DED) but do contain p20 and p10 domains.

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16
Q

How are caspases controlled?

A

Synthesised as procaspases (zymogens)- prodomain at N-terminus maintains inactivation. Proteolytic cleavage releases prodomain to form heterodimer.
Cleavage of the inactive procaspase precursor is followed by folding of 2 large and 2 small chains to form an active L2S2 heterotetramer.

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17
Q

What are the main purposes of caspase cascades?

A

Amplification
Divergent responses
Regulation

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18
Q

How is the apopototic programme triggered by caspase cascades?

A

Initiator caspases (8 and 9) trigger apoptosis by cleaving and activating effector caspases (1, 2, 3, 6 and 7) which carry out the apoptotic programme.

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19
Q

What is the role of effector caspases?

A 
Execute the apoptotic programme. 
Cleave and inactivate proteins or complexes (e.g. nuclear lamins- nuclear breakdown),
Activate enzymes (including protein kinases, e.g. caspase-activated DNase, CAD) by direct cleavage, or cleavage of inhibitory molecules.
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20
Q

What are the 2 mechanisms of caspase activation?

A

Death by design- receptor-mediated (extrinsic) pathway

Death by default- mitochondrial (intrinsic) death pathway

21
Q

What do death receptors consist of?

A 
Extracellular cysteine-rich domain
Single transcellular domain
Cytoplasmic tail (with a death domain)
22
Q

How are death receptors activated?

A

When they encounter secreted or transmembrane trimeric ligands, e.g. TNF-alpha or Fas- death ligands.

23
Q

What are the 2 important adaptor proteins in the extrinsic ‘death by design’ pathway?

A

FADD

FLIP

24
Q

What is FADD?

A 
Positive regulator (required for the death pathway to become activated), promotes cell death.
Death effector domain (DED) + death domain (DD).
25
Q

What is FLIP?

A 
Negative regulator (inhibits the death pathway and allows it to be regulated.
Death effector domain (DED) + DED.
26
Q

How does signalling occur through death receptors like the Fas/Fas-ligand?

A

Fas is a death receptor that is up-regulated if apoptosis is required.
Receptor (Fas) trimerisation by ligand (Fas-L on lymphocyte).
Recruitment of adaptor protein (FADD) through its DD to DD of Fas.
Recruitment and oligomerisation of procaspase 8 through its DED to FADD DED –> death-inducing signalling complex (DISC).

27
Q

What does oligomerisation of initiator procaspase 8 result in?

A

Cleavage and activation of initiator procaspase 8 to active initiator caspase 8 tetramer.

28
Q

How many procaspases are needed to form an active tetramer?

A

At least 2.

29
Q

What inhibits death receptor activation of caspase (procaspase 8 activation), and how?

A

FLIP- caspase homology in DED domain, but no proteolytic activity therefore competes with procaspase.
Competes for binding receptor tails/FADD via DED domains.
Incorporates into receptor-procaspase complexes and interferes with transcleavage.

30
Q

What factors can result in loss of mitochondrial membrane potential and thus mitochondrial regulation of (intrinsic) apoptosis?

A

Cellular stresses, e.g. lack of or overstimulation by growth factors, DNA damage (p53), reactive oxygen stress (ROS)

31
Q

What are the consequences of loss of mitochondrial membrane potential in mitochondrial regulation of (intrinsic) apoptosis?

A

Release of cytochrome c and other factors.
Release of other apoptosis-inducing factors.
Formation of the apoptosome complex (Apaf1, caspase 9).

32
Q

What is Apaf-1 and what does it consist of?

A

Apoptotic activating factor-1.

CARD, ATPase, WD-40 repeats (protein-protein interactions).

33
Q

What makes up the apoptosome (wheel of death)?

A

Apaf-1
Cytochrome c (binds to WD-40 repeats)
ATP
Procaspase 9 (binds to CARD)

34
Q

Is apoptosis an active or passive process?

A

Active- apoptosome requires ATP. Energy levels in the cell may determine whether death is by necrosis (passive) or apoptosis.

35
Q

What does caspase 3 trigger in apoptosis?

A

Cascade to proteolysis and cell death.

36
Q

How are the extrinsic and intrinsic pathways of apoptosis connected?

A 
Caspase 8 (extrinsic) and caspase 9 (intrinsic) both lead to production of caspase 3.
Caspase 8 (extrinsic) cleaves Bid, which enhances release of mitochondrial proteins, thus engaging the intrinsic pathway.
37
Q

What are the anti-apoptotic Bcl-2 family proteins (mitochondrial)?

A

Bcl-2

Bcl-xL

38
Q

What are the pro-apoptotic Bcl-2 family proteins (move between cytosol and mitochondria)?

A

Bid
Bad
Bax
Bak

39
Q

What is PI3’K?

A

Phosphatidylinositol 3’-kinase.

A lipid kinase (not protein kinase) involved in growth control and cell survival.

40
Q

What is the main difference between the intrinsic and extrinsic pathways of apoptosis?

A

Intrinsic pathway (mitochondrial) requires ATP- active process.

41
Q

What are Bcl-2 family proteins?

A

Intrinsic modulators of apoptosis.

42
Q

What is the BH3 domain?

A 
Common to all 3 groups of Bcl-2 family proteins.
Dimerisation motif (for protein-protein interaction)- allows proteins in the Bcl-2 family to associate and dimerise with each other.
43
Q

How does PKB/Akt induce cell survival?

A

By blocking apoptosis.
Phosphorylates and inactivates Bad and caspase 9.
Inactivates FOXO transcription factors (FOXOs promote expression of apoptosis-promoting genes).
Other, e.g. stimulates ribosome production and protein synthesis.

44
Q

How do IAPs regulate programmed cell death?

A

Inhibitors of apoptosis proteins.
Inhibit extrinsic pathway.
Bind to procaspases and prevent activation.
Bind to active caspases and inhibit their activity.

45
Q

What are the cytoprotective/anti-apoptotic pathways?

A

Bcl-2, Bcl-xL: regulate intrinsic pathway.
FLIP, IAPs: regulate extrinsic pathway.
Growth factor pathways via PI3’-K and PKB/Akt.

46
Q

How can programmed cell death be used therapeutically?

A

Harmful (oncogenic) cells, e.g. cells with viral infection, DNA damage.
Chemotherapeutic killing of tumour cells, e.g. dexamethasone stimulates DNA cleavage.

47
Q

What are the 3 main subunits of PI3’-K?

A

Targeting subunit
Adaptor subunit
Catalytic subunit

48
Q

What is the role of PTEN in apoptosis?

A

Lipid phosphatase that counteracts the production of PKB, therefore reducing the regulation of cell survival and promoting apoptosis.

MCD: Cancer (17 decks)

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